The present invention is related to core 1β3-galactosyl transferase specific molecular chaperones (“Cosmc-1”), and nucleic acids encoding the Cosmc-1 proteins, and to methods of use thereof.
The O-glycans in human glycoproteins and mucins are important in many aspects of cellular metabolism and cellular interactions, including those involved in leukocyte trafficking (1,2). The biosynthesis of mucin-type O-glycans in animal mucins and other glycoproteins is orchestrated by a set of N-acetylgalactosaminyl-transferases that transfer GalNAc to specific serine and threonine (Ser/Thr) residues to generate the sequence GalNAcα1-Ser/Thr, also known as the Tn antigen (3). Subsequently, this precursor is acted upon by the core 1 β3-galactosyltransferase (C1β3Gal-T) to generate the core 1 disaccharide O-glycan Galβ1-3GalNAcα1-Ser/Thr (4,5), also known as the T antigen or Thomson-Friedenrich antigen. Unlike most glycosyltransferases, which occur in gene families, a single human gene on 7p14-p13 encodes the C1β3Gal-T (4). Other core structures for mucin-type O-glycans are known, but core 1 is the common core structure found on human erythrocytes and most lymphocytes and it serves as a precursor for the branched core 2 O-glycans Galβ1-3(GlcNAcβ1-6)GalNAcα1-Ser/Thr found on human leukocytes (6). The factors regulating expression of core 1 are being intensely studied, since expression of Tn antigen is recognized as a tumor-associated antigen for breast and colon carcinomas (7,8), and the inability to generate the core 1 O-glycan is potentially a contributing factor to several autoimmune diseases, including IgA nephropathy (9), Tn-Syndrome (10), and Henoch-Schönlein purpura (11).
The human T leukemic cell line Jurkat cells lack C1β3Gal-T activity and generates truncated O-glycans bearing the Tn antigen (12, 13). Thus, a potential alteration in the expression of the C1β3Gal-T is predicted to have global changes on the O-glycan structures in multiple glycoproteins. As a result, there has remained a need in the field for complete identification of all steps and requirements for formation of fully active core 1 β3-galactosyl transferase. Such a need is hereby fulfilled as demonstrated hereinbelow.